Synthetic polyester surgical articles

ABSTRACT

A procedure is disclosed employing the sequential addition of monomers to form a copolymer useful in the manufacture of surgical articles.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part application of U.S. application, Ser. No.143,978 filed Apr. 28, 1980, which is a divisional of U.S. application,Ser. No. 960,264 filed Nov. 13, 1978, which is a continuation-in-part ofU.S. application, Ser. No. 799,836 filed May 23, 1977 now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a new and useful method for preparingsynthetic polyester surgical articles, as well as the articles producedthereby and methods for using them.

The use of cyclic ester monomers in the formation of polyesters for thefabricating of synthetic surgical articles is well known in the art. Inconjunction therewith, comonomers have often been employed to modify thecharacteristics of the various polyesters.

The conventional polymerization method for forming polymers of thecyclic esters is through ring opening polymerizations. Usually, wherecopolymers are prepared, one cyclic ester is copolymerized with another.

The use of monomers in the formation of polyester surgical articles isdiscussed in a variety of patents and technical publications. Usefulpolymerization and post-treatment methods as well as fabricationprocedures for the surgical articles are also well known. The surgicalarticles produced include both absorbable and non-absorbable articles.

The following patents and technical articles and references citedtherein are of interest in this respect:

(1) U.S. Pat. Nos.--3,268,486-7; 3,297,033; 3,442,871; 3,463,158;3,620,218; 3,626,948; 3,739,773; 3,839,297; 3,875,937; 3,896,802;3,937,223; 3,728,839; 3,531,561; 3,867,190; 3,784,585.

(2) Foreign Pat. Nos.--1,332,505; 1,414,600 (British), and 776,980;778,126; 788,116 (Belgian).

(3) Technical Articles--Developement of a Synthetic Polymer BurnCovering; by John B. Gregory et al; DYNATECH R/D COMPANY in conjunctionwith Department of the Navy, Contract No. N00014-73-C-0201; March 30,1973;

Developement of a Synthetic Polymer Burn Covering; by John B. Gregory etal; DYNATECH R/D COMPANY in conjunction with Department of the Navy,Contract No. N00014-73-C-0201; June 8, 1973;

Developement of a Synthetic Polymer Burn Covering; by A. D. Schwope etal; DYNATECH CORPORATION in conjunction with Department of the Navy,Contract Authority NR 104-702/10-3-72 (444); January 31, 1974.

D. E. Cutright et al, Oral Surg. Vol. 31, No. 1, p. 134-9, Jan. 1971;Vol. 32 No. 1, p. 165-173, July 1971 and Vol. 37, No. 1, p. 142-152,January 1974.

July 25, 1972, Report by R. G. Sinclair and G. W. Gynn entitledPreparation and Evaluation of Glycolic and Lactic Acid Based PolymersFor Implant Devices Used In Management of Maxillofacial Trauma,published in conjunction with Contract No. DADA17-72-C-2066. Supportedby the U.S. Army Medical Research and Development Command.

As mentioned as conjunction with U.S. Pat. No. 3,867,190 and its parentpatent applications the biological inertness of the polylactic acidsutures prepared with the hope of being absorbable in living tissue wasmodified by incorporation of glycolic acid units in the polymer chain.Unfortunately, the copolymers formed by coreacting increasing amounts ofglycolide with the lactide were said to have the disadvantage of formingsurgical articles which lacked dimensional stability in-vivo.

SUMMARY OF THE INVENTION

This invention describes an improved method for the manufacture ofsterile surgical articles fabricated from a synthetic absorbablecopolymer formed by copolymerizing glycolide monomer with a cyclic estermonomer other than glycolide. The improvement comprises employingsequential addition of the monomers in the polymerization, wherein theglycolide monomer, the cyclic ester monomer, or a combination of themonomers is substantially completely polymerized before the addition ofthe other monomer or combination. In the preferred method the cyclicester monomer is lactide. In the most preferred method, the lactide isL(-)lactide.

In another preferred method the cyclic ester monomer is selected fromthe group consisting of lactones, oxalates or carbonates. In the mostpreferred method, the cyclic ester monomer is 1,4-dioxane-2,3-dione or1,3-dioxane-2-one.

This invention also describes a sterile surgical article fabricated froma synthetic absorbable copolymer prepared according to the methoddescribed above. In a preferred embodiment, the sterile surgical articleis in the form of a suture or a ligature. In a most preferredembodiment, the sterile surgical article is in the form of a needle andsuture combination.

This invention also describes a copolymer comprising a proportion ofsequential units having the formula: ##STR1## and a proportion ofsequential units having the formula: ##STR2## The end groups which couldbe used with this copolymer are well known in the art. These end groupsinclude, but are not limited to, lauryl, hydroxyl and carboxyl. Apreferred copolymer has a melting point of about 217° C. to 221° C. asdescribed by the peak in a differential scanning calorimeter operatingat a heating rate of 10° C. per minute. In addition to the melting pointcharacteristic, another embodiment is a copolymer having an inherentviscosity of about 0.5 dl/g. (deciliter per gram) to 2 dl/g. Stillanother embodiment is a copolymer having an inherent viscosity of about0.7 dl/g to 1.2 dl/g.

Within the scope of this invention is a copolymer described abovewherein formula (II) consists of between about 1% to 99% by weight. Anarrower embodiment is a copolymer described above wherein formula (II)consists of up to about 50% by weight. Another embodiment is a copolymerdescribed above wherein formula (II) consists of up to about 35% byweight. Still another embodiment is a copolymer described above whereinformula (II) consists of between about 10% to 20% by weight.

Also within the scope of this invention is a sterile surgical articlefabricated from a synthetic absorbable copolymer as described above. Ina preferred embodiment, the sterile surgical article is in the form of asuture or ligature. In a most preferred embodiment, the sterile surgicalarticle is in the form of a needle and suture combination.

A method of retaining living tissue in a desired relationship during ahealing process by positioning and emplacing living tissue with asterile surgical article fabricated from a synthetic absorbablecopolymer as described above is also within the scope of this invention.Finally, a method of closing a wound of living tissue which comprisessewing the edges of the wound with a sterile surgical article in theform of a needle and suture combination as described above is within thescope of this invention.

DESCRIPTION OF THE INVENTION

It has now been found that synthetic polyester surgical articles canadvantageously be manufactured by employing in conjunction therewith apolymerization procedure whereby a copolymer is formed through a ringopening polymerization wherein the polymerization is sequentially orincrementally carried out. This is achieved by consecutively adding themonomers used to form the copolymer chain. By conducting thepolymerization procedure in a stepwise or staged manner, the in vivocharacteristics of the surgical articles produced can more broadly bemodified prior to encountering the usual degree in interference of theability of the polymer to form dimensionally stable, highly crystalline,or highly oriented molecular structures.

The process of the present invention can be employed in two or morestages using two or more monomers in the polymerization procedure. Inone or more of the stages, two monomers can be employed simultaneously.A different catalyst may be employed at each stage if desired.

It is generally preferred to conduct the consecutive polymerizations inthe same reaction vessel by sequentially adding the monomers thereto;however, if desired one or more of the polymer segments can be preparedand used as such for further chemical reaction to form the finalcopolymer in a different reaction vessel of choice while still retainingthe advantages of and falling within the present invention.

The two monomers conventionally preferred for use in preparing surgicalarticles are L(-) lactide and glycolide. They are also preferred for usein the present invention. Furthermore, it is generally preferred,herein, to employ them together in a sequential polymerizationprocedure. A second monomer pair preferred for use in the presentinvention is trimethylene carbonate/glycolide.

One or more of the following intramolecular cyclic esters may also beused as one of the monomers to copolymerize with glycolide in thepractice of the present invention: β-propiolactone, β-butyrolactone,gamma-butyrolactone, 2-keto-1,4-dioxane, delta-valerolactone,epsilon-caprolactone, pivalolactone, α,α-diethylpropiolactone,2,5-diketomorpholine, 6,8-dioxabicyclo[3,2,1]-octane-7-one, ethylenecarbonate, ethylene oxalate, 3-methyl-1,4-dioxane-2,5-dione,3,3-dimethyl-1,4-dioxane-2,5-dione; and intermolecular cyclic diestersof α-hydroxybutyric acid, α-hydroxyvaleric acid, α-hydroxyisovalericacid, α-hydroxycaproic acid, α-hydroxy-α-ethylbutyric acid,α-hydroxyisocaproic acid, α-hydroxy-α-methyl-valeric acid,α-hydroxyheptanoic acid, α-hydroxyoctanoic acid, α-hydroxydecanoic acid,α-hydroxymyristic acid, α-hydroxystearic acid, α-hydroxylignoceric acidand salicylic acid.

As mentioned above, one of the preferred areas for use of the presentinvention relates to the preparation of sterile, synthetic, absorbable,surgical articles (especially sutures) wherein glycolide is employed asthe predominant monomer in preparing the polyesters. The present stateof the art is such that detailed absorption mechanisms and details ofthe polymer structures on the molecular levels are not known withcertainty.

One of the preferred embodiments of the present invention relates tosequentially copolymerizing lactide [preferably L(-) lactide] withglycolide. Triblock structures formed by sequentially and consecutivelycopolymerizing L(-) lactide, glycolide and L(-) lactide respectively arealso of interest. In the latter case, the copolymer produced has lacticacid units predominating on both ends of the glycolide polymer chain.

Another preferred embodiment of the present invention relates tocopolymers of trimethylene carbonate and glycolide. Monofilament suturesfabricated from such copolymers have been found to be surprisinglyuseful in that they are more resistant to in-vivo strength loss thansimilar sutures fabricated from polyglycolide.

It is believed that the three usual morphological units, namely spheres,rods (or cylinders) and lamellae which are well known in AB and ABA typecopolymers, e.g., poly(styrene-b-butadiene) (PSB) would be exhibited inthe copolymers of the present invention. In films of PSB where the moleratio of styrene units to butadiene units is 80/20, spherical domainshave been observed by electron microscopy. As the mole ratio decreaseswith relatively greater quantities of butadiene units the morphology ofthe microphase separation is altered from spheres of butadiene units ina matrix of styrene units to rods of butadiene units in a matrix ofstyrene units and then to alternate lamellae of the units. When the moleratio is further decreased until the butadiene predominates, the styreneunits are first presented as a cylindrical or rod like microphaseseparations in a matrix of butadiene units whereafter, as the mole ratiois further decreased, the styrene units are presented as spheres in amatrix of butadiene units. (See M. Matsuo, S. Sagae and H. Asai,Polymer, 10, 79, 1969).

As mentioned above, in the preparation of absorbable sutures, inaccordance with the practice of the present invention one may employpolyesters wherein minor amounts of a chain segment formed from anothermonomer such as L(-) lactide or trimethylene carbonate is incorporatedat one or both ends of a chain of glycolide units.

It is to be understood that employing sequential addition of a cyclicester other than glycolide which is substantially completely polymerizedbefore the addition of glycolide is within the practice of the presentinvention. The addition of trimethylene carbonate followed by theaddition of glycolide is preferred.

The surgical articles are fabricated from the copolymer usingconventionally employed procedures. All of the above patents andtechnical articles are incorporated herein by reference. Likewise, theresulting surgical articles are employed in a conventional manner.

The following examples illustrate procedures which are useful inconjunction with the practice of the present invention but are not to betaken as being limiting thereof. Unless otherwise specified, all partsand percentages mentioned herein are by weight. In all of the examples,where not indicated, inherent viscosity (or I.V.) is measured using asolution of 0.5 grams of copolymer per 100 milliliters ofhexafluoroacetone sesquihydrate (HFAS) at 30° C.

EXAMPLES 1-2

An ether solution of SnCl₂.2H₂ O and an ether solution of lauryl alcoholwere prepared. A sufficient volume of the above solutions was added totwo polymerization tubes so that when the solvent was removed the finalweights of SnCl₂.2H₂ O and lauryl alcohol per 20.0 g of L(-) lactidemonomer were as indicated in Table I:

                  TABLE I                                                         ______________________________________                                        Tube No. mg Sn Cl.sub.2 . 2 H.sub.2 O                                                                  mg Lauryl Alcohol                                    ______________________________________                                        1        2.0             125                                                  2        4.0             250                                                  ______________________________________                                    

After the solvent was removed, 20.0 g of L(-) lactide was added to eachtube. The tubes were evacuated and sealed under vacuum. They were thenplaced in an oil bath at 180° C. for 24 hours. They were removed fromthe oil bath and let cool to room temperature. The tubes were opened,the polymer ground in a Wiley mill through a 20 mesh screen and driedfor 24 hours at 50° C. at 0.1 mm Hg. The resultant polymers from tubes 1and 2 were formed in 86% and 89% conversion and had I.V.'s of 0.33 and0.27, respectively. The present conversion to polymer was obtained bydividing the weight of polymer after drying by the weight of polymerbefore drying. I.V. means the inherent viscosity of a solution of 0.5 gof dried polymer/100 ml of hexafluoroacetone sesquihydrate, measured at30° C.

Into a three neck 100 ml round bottom flask equipped with a glass shaftand Teflon® paddle stirrer, attached to a stirring motor and a gas inlettube connected to an argon cylinder, was added 7.0 g of the 0.33 I.V.poly L(-) lactide described above. The flask was flushed with argon gasfor 15 minutes. The flush was maintained throughout the polymerization.The flask was placed in a 190° C. oil bath. The pot contents reached180°±2° C. within 15 minutes. Then 3.5 g of glycolide was added withstirring and the oil bath temperature was adjusted to keep thetemperature of the pot contents at 180°±2° C. for 30 minutes withcontinuous stirring. The temperature of the oil bath was then raised sothat during 30 minutes the temperature of the pot contents reached220°±2° C. Then the remainder of the glycolide, 31.5 g, was added andthe temperature of the pot contents was maintained at 220°±2° C. for11/2 hours with continuous stirring. At that time the oil bath wasremoved, the stirring was stopped, and the pot contents were allowed tocool to approximately room temperature under the argon flush. This flushwas then stopped. The glass flask was then broken and the polymer wasremoved and ground in a Wiley mill through a 20 mesh screen. A portion(3.0 g) of the ground polymer was dissolved in 60 ml ofhexafluoroacetone sesquihydrate (HFAS) at 60° C. The polymer wasprecipitated by dripping this solution into 600 ml of methanol withstirring. The polymer was collected by filtration and extracted withacetone in a Soxhlet extractor for 2 days to remove the residue offluorinated solvent. The polymer was then dried in a vacuum ovenovernight at 50° C. at 0.1 mm Hg. The yield of polymer was 95%. The I.V.in HFAS was 0.77. The mole percent of the lactic acid units in thepolymer chain as determined by NMR was 8.8. The melting point asdetermined from the peak endotherm observed in a differential thermalanalysis (D.T.A.) apparatus was 218° C.

A second two-stage copolymer was prepared as follows. Into a three neck100 ml round bottom flask equipped with a glass shaft and a Teflon®paddle stirrer attached to a stirring motor, and a gas inlet tubeconnected to an argon cylinder, was added 4.0 g of the poly L(-) lactidewhose I.V. was 0.27, with stirring. This was flushed with argon gas for15 minutes. This argon gas flush was maintained throughout the followingpolymerization. The flask was placed in a 190° C. oil bath. The potcontents reached 180°±2° C. within 15 minutes. Then, 3.6 g of glycolidewere added with stirring and the oil bath temperature was adjusted tokeep the temperature of the pot contents at 180°±2° C. for 30 minuteswith continuous stirring. The temperature of the oil bath was thenraised so that at the end of 30 minutes the temperature of the potcontents reached 220°±2° C. Then, 31.4 g of glycolide was added and thetemperature of the pot contents was maintained at 220°±2° C. for 11/2hours with continuous stirring. At this time the oil bath was removed,the stirring was stopped and the pot contents were allowed to cool toapproximately room temperature under the argon flush. The flush was thenstopped. The glass flask was broken and the polymer was removed andground in a Wiley mill through a 20 mesh screen. 3.0 g of this polymerwere dissolved in 60 ml of 60° C. hexafluoroacetone sesquihydrate (HFAS)and the polymer was precipitated by dripping this solution into 600 mlof methanol with stirring. The polymer was collected by filtration andextracted with acetone in a Soxhlet extractor for 2 days. The polymerwas then dried in a vacuum oven overnight at 50° C. at 0.1 mm Hg. Theyield of polymer was 95%. The I.V. in HFAS was 0.82. The mole precent oflactic acid units in the polymer as determined by NMR was 5.9. Themelting point as determined by the peak endotherm observed in a D.T.A.apparatus was 219° C.

EXAMPLE 3

A sample of poly L(-) lactide was prepared by the procedure of Examples1-2 except that it was formed in 98% conversion with a 0.5 I.V. using1.2 mg of Sn Cl₂.2H₂ O and 7.5 mg of lauryl alcohol. Into a three neck100 ml round bottom flask equipped with a glass shaft and a Teflon®paddle stirrer attached to a stirring motor and a gas inlet tubeattached to an argon cylinder, was added 10.0 g of the poly L(-)lactide. This was flushed with argon for 15 minutes. This argon flushwas maintained through the following polymerization. The flask wasplaced in a 190° C. oil bath. The pot contents reached 180°±2° C. with15 minutes. Then 2 g of glycolide was added with stirring and the oilbath temperature was adjusted to keep the temperature of the potcontents at 180°±2° C. for 30 minutes with continuous stirring. Thetemperature of the oil bath was then raised so that at the end of 30minutes the temperature of the pot contents reached 220°±2° C. Then,18.0 g of glycolide were added and the temperature of the pot contentswas maintained at 220°±2° C. for 11/2 hours with continuous stirring. Atthis time the oil bath was removed, the stirring was stopped and the potcontents were allowed to cool to approximately room temperature underargon flush. This flush was then stopped. The glass flask was broken andthe polymer was ground up in a Wiley mill through a 20 mesh screen.

20.0 g of this polymer was dissolved in 400 ml of 60° C.hexafluoroacetone sesquihydrate (HFAS) and the polymer was precipitatedby dripping this solution into 4,000 ml of methanol with stirring. Thepolymer was collected by filtration and extracted with acetone in aSoxhlet extractor for 2 days. The polymer was then dried in a vacuumoven overnight at 50° C. at 0.1 mm Hg. The yield of polymer was 72%. TheI.V. in HFAS was 0.60. The mole percent of lactic acid units in thepolymer as determined by NMR was 33. The melting point as determinedfrom the peak endotherm observed in a differential thermal analysis(D.T.A.) apparatus was 219° C.

EXAMPLE 4

Into a three neck 100 ml round bottom flask equipped with a glass shaftand a Teflon® paddle stirrer attached to a stirring motor and a gasinlet tube attached to an argon cylinder, was added 6.0 g of a 0.29 I.V.poly L(-) lactide prepared as in Example 3 except that a heating periodof 1.5 hours at 200° C. was used. The flask was flushed with argon for15 minutes. This argon flush was maintained throughout the followingpolymerization. The flask was placed in a 200° C. oil bath and the bathtemperature was raised until the temperature of the pot contents reached200°±2° C. This occurred within 15 minutes. Then, 48.0 g of glycolidewere added with stirring and the temperature of the oil bath was raiseduntil the temperature of the pot contents was 225°±2° C. This occurredwithin 30 minutes. Stirring was continued for 11/2 hours at thistemperature. Then, 6.0 g of L(-) lactide were added (with stirring ofthe pot contents) and stirring was continued 11/2 hours at thistemperature. At this time, the oil bath was removed, the stirring wasstopped and the pot contents were allowed to cool to approximately roomtemperature under the argon flush. This flush was then stopped. Theglass flask was broken and the polymer was removed and ground in a Wileymill through a 20 mesh screen. 5.0 g of this polymer were dissolved in100 ml of hexafluoroacetone sesquihydrate (HFAS) and the polymer wasprecipitated by dripping this solution in 1,000 ml of methanol withstirring. The polymer was collected by filtration and extracted withacetone in a Soxhlet extractor for 2 days. The polymer was dried in avacuum oven overnight at 50° C. at 0.1 mm Hg. The yield of polymer was82%. The I.V. in HFAS was 0.81. The mole percent of lactic acid units inthe polymer chain as determined by NMR was 11.2. The melting point asdetermined from the peak endotherm in a differential thermal analysis(D.T.A.) apparatus was 216° C.

EXAMPLE 5

Into a three neck 100 ml round bottom flask equipped with a glass shaftand a Teflon® paddle attached to a stirring motor and a gas inlet tubeattached to an argon cylinder, was added 4.5 g ofpoly(epsilon-caprolactone) whose I.V. was 0.42. Thepoly(epsilon-caprolactone) polymer was prepared as in Example 1 exceptthat 8.0 mg of SnCl₂.2H₂ O and 500 mg of lauryl alcohol were employedand epsilon-caprolactone was used in place of the L(-) lactide. Theflask was flushed with argon for 15 minutes. The argon flush wasmaintained throughout the following polymerization. The flask was placedin a 190° C. oil bath. The pot contents reached 180°±2° C. within 15minutes. Then, 1.35 g of glycolide were added with stirring and the oilbath temperature was adjusted to keep the temperature of the potcontents at 180°±2° C. for 30 minutes with continuous stirring. Thetemperature of the oil bath was then raised so that at the end of 30minutes the temperature of the pot contents was 220°±2° C. Then, 12.15 gof glycolide were added with stirring and the temperature of the potcontents was maintained at 220°±2° C. for 11/2 hours with continuousstirring. At this time the oil bath was removed, the stirring wasstopped and the pot contents were allowed to cool to approximately roomtemperature under the argon flush. This flush was then stopped. Theglass flask was broken and the polymer was removed and ground in a Wileymill through a 20 mesh screen. 4.0 g of this polymer was dissolved in 80ml of 60° C. HFAS and the polymer was precipitated by dripping thissolution into 1000 ml of methanol with stirring. The polymer wascollected by filtration and extracted with acetone in a Soxhletextractor for 2 days. The polymer was then dried overnight in a vacuumoven at 50° C. at 0.1 mm Hg. The yield of polymer was 73%. The I.V. inHFAS was 0.77. The mole percent of epsilon-hydroxy caproic acid units inthe polymer chain as determined by NMR was 12.3. This corresponds to12.1 weight percent caprolactone units. The melting point as determinedfrom the peak endotherm in a differential thermal analysis (D.T.A.)apparatus was 218° C.

EXAMPLE 6

Into a three neck 100 ml round bottom flask equipped with a glass shaftand a Teflon® paddle attached to a stirring motor and a gas inlet tubeattached to an argon cylinder was added 7.0 g of poly(trimethylenecarbonate) whose I.V. was 0.34. The poly(trimethylene carbonate) wasprepared by the procedure of Example 1 except that trimethylenecarbonate was used in place of the L(-) lactide and 4.0 mg of SnCl₂.2H₂O was used with 250 mg of lauryl alcohol; the conversion was 48%.

The flask was flushed with argon for 15 minutes. The argon flush wasmaintained throughout the following polymerization. The flask was placedin a 190° C. oil bath. The pot contents reached 180°±2° C. within 15minutes. Then, 3.5 g of glycolide were added with stirring and the oilbath temperature was adjusted to keep the temperature of the potcontents at 180°±2° C. for 30 minutes with continuous stirring. Thetemperature of the oil bath was then raised so that at the end of 30minutes the temperature of the pot contents was 220°±2° C. Then, 31.5 gof glycolide were added with stirring and the temperature of the potcontents was maintained at 220°±2° C. for 11/2 hours with continuousstirring. At this time the oil bath was removed, the stirring wasstopped and the pot contents were allowed to cool to approximately roomtemperature under the argon flush. This flush was then stopped. Theglass flask was broken and the polymer was removed and ground in a Wileymill through a 20 mesh screen. 5.0 g of this polymer were dissolved in100 ml of 60° C. HFAS and the polymer was precipitated by dripping thissolution into 1,000 ml of methanol with stirring. The polymer wascollected by filtration and extracted with acetone in a Soxhletextractor for 2 days. The polymer was dried overnight in a vacuum ovenat 50° C. at 0.1 mm Hg. The yield of polymer was 86%. The I.V. in HFASwas 0.64. The mole percent of units derived from trimethylene carbonatein the polymer chain as determined by NMR was 16.4. This figurecorresponds to 14.7 weight percent trimethylene carbonate units. Themelting point as determined from the peak endotherm in a differentialthermal analysis (D.T.A.) apparatus was 218° C.

EXAMPLE 7

Trimethylene carbonate (39 g.), SnCl₂.2H₂ O (3.3 mg.) and lauryl alcohol(0.133 g.) were added to a stirred reactor which had been preheated to153° C. under a stream of nitrogen. The temperature was increased over a30 minute period to 180° C. After stirring an additional 30 minutes atthat temperature a 2.5 g. sample was withdrawn and glycolide (17 g.) wasadded. The temperature was then raised over a 30 minute period to 223°C. After stirring the mixture for 45 minutes at this temperature, moreglycolide (153 g.) was added. Stirring was continued for one hour atthis temperature at which point the polymer was discharged. The polymerwas cooled and ground finely enough to pass through a 10 mesh screen,and was then dried for 48 hours at 140° C. (0.25 mmHg).

The 2.5 g sample of poly(trimethylene carbonate) removed at 180° C. wasdissolved in methylene chloride. The solution was added dropwise tomethanol and the precipitated polymer was collected and dried 24 hoursat 40° C. (0.25 mgHg). The resulting homopolymer had an inherentviscosity of 1.32 (30° C., 0.5% solution) in H.F.A.S.

The inherent viscosity of the final copolymer was 0.81. Theconcentration of trimethylene carbonate units in the copolymer was foundby NMR analysis to be 17 mole percent or 15% by weight. Usingdifferential scanning calorimetry, the glass transition temperature wasfound to be 32° C. and the peak of the melting endotherm was found at216° C.

EXAMPLE 8

The copolymer of Example 7 was extruded at a temperature of 230° C. atthe rate of 0.5 lbs/hr through a 30 mil capillary having a length todiameter ratio of 4 to 1. The extrudate was passed through a waterquench bath at room temperature and collected on a bobbin at the rate of200 feet per minute.

The resulting extrudate was then drawn through a hot air chamber set at40° C. at a rate of 10 feet per minute and a draw ratio of 5.2X, to forma monofilament falling in the USP size 6/0 range.

The physical properties of the drawn fiber were:

    ______________________________________                                        Straight Pull Tensile Strength:                                                                     98,600 psi                                              Straight Pull Elongation At Break:                                                                  35%                                                     Knot Pull Strength:   78,600 psi                                              Modulus:              1,300,000 psi                                           Diameter:             0.096mm                                                 ______________________________________                                    

EXAMPLE 9

Samples of the monofilament of Example 8 were implanted subcutaneouslyin rats. After 21 days the samples were removed and their straight pulltensile strength was measured on an Instron Universal Testing MachineModel 1125 (Instron Corp., Canton, MA., U.S.A.). The samples retained,as an average, 45% of their original straight pull tensile strength.

EXAMPLE 10

Trimethylene carbonate (20 g), SnCl₂.2H₂ O (4 mg.) and lauryl alcohol(0.199 g) were added to a stirred reactor which had been preheated to140° C. The reaction mixture was stirred for two hours at thistemperature under a nitrogen atmosphere at which time a vacuum of 50 mm.Hg was applied and maintained for 30 minutes. The vacuum was releasedwith nitrogen and glycolide (180 g), preheated at 140° C., was addedunder nitrogen flow. The reactor was then heated over a 30 minute periodto a temperature of 220° C. The temperature was held at 220°-222° C. foran additional 45 minutes at which point the polymer was discharged. Thepolymer was cooled, cut into small pieces and dried for 24 hours at 130°C. (1 mmHg).

The inherent viscosity of the polymer was found to be 0.86, measured at30° C. in a 0.5% solution in hexafluoroacetone sesquihydrate (HFAS). Theconcentration of trimethylene carbonate units in the copolymer was foundto be 9 mole percent by NMR. This figure corresponds to 8 weight percenttrimethylene carbonate units. Using differential scanning colorimetry,the glass transition temperature was found to be 37° C.; the meltingrange was 196°-225° C., the peak of the melting endotherm occurred at221° C. and ΔH_(f) (the heat of fusion) was 17.6 cal./g. A portion ofthe polymer (130 g) was further treated by heating for three days at180° C. (0.2 mmHg) under a nitrogen flow of 2 cubic feet per hour. Thefinal product weighed 120 g, had an inherent viscosity of 0.96 andcontained 8.3 mole percent (7.4 weight percent) of trimethylenecarbonate units.

EXAMPLE 11

The copolymer of Example 10 was extruded at a temperature of 230° C.through a 60 mil capillary having a length to diameter ratio of 4 to 1.The extrudate was passed through a water quench bath at room temperatureand collected on a bobbin at the rate of 50 feet per minute. Theresulting extrudate was then drawn 8X through a hot air chamber set at50° C. The physical properties of the drawn fiber were:

    ______________________________________                                        Straight Pull Tensile Strength:                                                                     71,500 psi                                              Straight Pull Elongation At Break:                                                                  31%                                                     Knot Pull Strength:   54,400 psi                                              Modulus:              1,280,000 psi                                           Diameter:             0.164 mm                                                ______________________________________                                    

EXAMPLE 12

Trimethylene carbonate (98.0 g.), SnCl₂.2H₂ O (1.9 mg.) and laurylalcohol (74.8 mg.) were added to a stirred reactor which had beenpreheated to 172° C. under a stream of nitrogen. The temperature wasraised to 186° C. over a 1 hour period. A 3.6 g. sample was withdrawnand glycolide (14.0 g.) was added. The temperature was raised over a 10minute period to 200° C. More glycolide (90.0 g) was added. Thetemperature was then raised to 221° C. over the next 25 minutes at whichpoint the polymer was discharged. The polymer was cooled and groundfinely enough to pass through a 10 mesh screen, and was then dried for48 hours at 130° C. (<1 mmHg).

The 3.6 g. sample removed at 186° C. had an inherent viscosity of 2.21(30° C., 0.5% solution) in CH₂ Cl₂.

The inherent viscosity of the final copolymer was 0.94 in H.F.A.S. Theconcentration of trimethylene carbonate units in the copolymer was foundby NMR analysis to be 48.5 mole percent of 45.3% by weight. Usingdifferential scanning calorimetry, the glass transition temperatureswere found to be -5° and 34° C. and the peak of the melting endothermwas found at 216° C.

EXAMPLE 13

Trimethylene carbonate (125.0 g.), SnCl₂.2H₂ O (1.9 mg.) and laurylalcohol (74.8 mg.) were added to a stirred reactor which had beenpreheated to 153° C. under a stream of nitrogen. The temperature wasraised to 192° C. over a 75 minute period. A 2.6 g. sample was withdrawnand glycolide (10.0 g) added. The temperature was raised to 198° C. over10 minutes at which point more glycolide (85.0 g.) was added. Thetemperature was then raised to 220° C. over 10 minutes and the polymerdischarged. The polymer was cooled and ground finely enough to passthrough a 10 mesh screen, and was then dried for 48 hours at 130° C. (<1mmHg).

The 2.6 g sample withdrawn at 192° C. had an inherent viscosity of 1.28(30° C., 0.5% solution) in CH₂ Cl₂.

The inherent viscosity of the final copolymer was 1.07 as measured inH.F.A.S. The concentration of trimethylene carbonate units in thecopolymer was found by NMR analysis to be 57.4 mole percent or 54.2% byweight. Using differential scanning calorimetry, the glass transitionswere found to be 2° and 29° C. and the peak of the melting endotherm wasfound at 212° C.

EXAMPLE 14

The copolymer of Example 12 was extruded essentially as described inExample 8. The physical properties of the drawn monofilament were:

    ______________________________________                                        Straight Pull Tensile Strength:                                                                     26,000 psi                                              Straight Pull Elongation At Break:                                                                  16%                                                     Knot Pull Strength:   14,000 psi                                              Modulus:              479,000 psi                                             Diameter:             0.286 mm                                                ______________________________________                                    

EXAMPLE 15

The copolymer of Example 13 was extruded essentially as described inExample 8. The physical properties of the drawn monofilament were:

    ______________________________________                                        Straight Pull Tensile Strength:                                                                     26,000 psi                                              Straight Pull Elongation At Break:                                                                  50%                                                     Knot Pull Strength:   28,000 psi                                              Modulus:              203,000 psi                                             Diameter:             0.265 mm                                                ______________________________________                                    

EXAMPLE 16

Samples of the monofilament of Example 14 were implanted subcutaneouslyin rats. After 42 days the samples were removed and their straight pulltensile strength was measured as described in Example 9. The samplesretained, as an average, 38% of their original straight pull tensilestrength.

EXAMPLE 17

Samples of the monofilament of Example 15 were implanted subcutaneouslyin rats. After 42 days the samples were removed and their straight pulltensile strength was measured as described in Example 9. The samplesretained, as an average, 35% of their original straight pull tensilestrength.

EXAMPLE 18

L(-) lactide (1612 g), SnCl₂.2H₂ O (0.204 g) and lauryl alcohol (4.77 g)were added to a stirred reactor which had been preheated to 140° C. Thereactants were heated with stirring under a nitrogen atmosphere over a30 minute period to 200° C. and then held at that temperature for 2hours.

The reactor was evacuated to a pressure of 50 mmHg and the mixture wasstirred for 30 minutes during which time the temperature of the mixturewas allowed to fall to 180° C.

Atmospheric pressure was restored by introducing nitrogen into thereaction vessel and the temperature was raised to 200° C. over a 5minute period. The molten glycolide (5198 g) preheated to 100° C. wasadded and the temperature was raised over a 15 minute period to 225° C.and held at this temperature for an additional 20 minutes.

The contents of the reactor were discharged and the polymeric mass wasbroken up after it had cooled to room temperature. The polymer was thenground and vacuum dried at 8-10 mmHg for 11 hours at 140° C. to removeall volatiles preparatory to spinning and determining the polymer'sviscosity.

The inherent viscosity of the polymer was determined to be 1.14,measured at 30° C. in a 0.5% solution in hexafluoroacetonesesquihydrate. The mole % of lactic acid units in the finished polymerwas determined to be 20.3% by NMR. The melting range of the product wasdetermined to be 215°-223.5° C. using a hot stage polarizing microscope.

A portion of the dried polymer was added to the feed hopper of a smallcontinuous extruder operating at about 230° C. The extruder was equippedwith a die having a 60 mil cylindrical orifice and a length to diameterratio of 4 to 1. The extrudate was water quenched and collected at 44feet per minute. It was then drawn to about 4.5 times its originallength at 55° C. in a hot air draw unit. A sample of glycolidehomopolymer having a 1.05 I.V. was extruded and drawn in the same wayand then post-treated along with the above copolymer fiber, for 3 hoursat 135° C. at a pressure of 1 mmHg.

The copolymer fiber which was 2.45 mils in diameter was found to haveexceptional tensile-strength retention properties (34,600 p.s.i.) in anaccelerated strength retention test and very good initial tensilestrength (96,500 p.s.i.) notwithstanding its high comonomer content(20.3 mole%). In the contrast, the initial strength of the homopolymerfiber which was 2.10 mils in diameter was 140,000 p.s.i. and thecounterpart strength retained in an accelerated test was 25,300 p.s.i.

As mentioned above, it is believed that such copolymeric polyesters arecharacterized by microphase separations having spherical domains in themolten state, prior to orientation wherein the chain segments composedof lactic acid units are overlapped with themselves in a matrix ofglycolic acid units. It is believed that polyesters having suchmicrophase separation would exist where the mole percentage of L(-)lactide incorporated into the polymer chains ranged up to about 25percent. From about 25 percent to about 40 percent lactic acid units itis believed that cylindrical domains of lactic acid units wouldpredominate. This would likewise be the case where the lactic acid unitsprevailed on both ends of the polyester chains as a result ofsequentially and consecutively polymerizing L(-) lactide, glycolide andthen L(-) lactide.

Although the geometry of the domains in the molten state is speculative,evidence for the existence of phase separation or precipitation of thepolymers may be seen by comparing their melting points with that of thehomopolymer of the major component.

Accordingly, preferred surgical articles prepared in accordance with thepresent invention are sterile synthetic absorbable surgical suturesprepared from a lactide polyester said polyester being composed of acopolymer having cylindrical or more preferably spherical dominions ofL(-) lactide units in a matrix of glycolide units. The polyestersemployed can have the relative quantities of glycolide units and L(-)lactide units indicated above. The sutures may be in the form of asterile surgical needle and suture combination. Conventional suturecontructions and sterilization methods may be used. Preferably amonofilament or polyfilamentary braided polyester yarn is crimped intothe butt of a surgical needle and the needled suture is then sterilizedusing a toxicant such as ethylene oxide. Polyesters formed bysequentially and consecutively polymerizing L(-) lactide and glycolideare most preferred for use therein.

While the surgical articles of the present invention are generallyuseful in conventional manners for retaining living tissue in a desiredlocation and relationship during a healing process by positioning andemplacing living tissue therewith, as in ligation of blood vessels, theneedled sutures are especially adapted for the closing of wounds ofliving tissue by sewing together the edges thereof using conventionalsuturing techniques.

We claim:
 1. A sterile surgical article fabricated from a syntheticabsorbable copolymer formed by copolymerizing glycolide as thepredominant monomer with a cyclic ester monomer other than glycolide,the improvement comprising employing sequential addition of the monomersin the polymerization wherein said glycolide monomer, said cyclic estermonomer, or a combination of said monomers is substantially completelypolymerized before the addition of the other monomer or saidcombination.
 2. An article according to claim 1 wherein said cyclicester monomer is L(-) lactide.
 3. An article according to claim 1wherein said cyclic ester monomer is selected from the group consistingof lactones, oxalates or carbonates.
 4. An article according to claim 3wherein said cyclic ester monomer is 1,3-dioxan-2-one.
 5. An articleaccording to claim 1 wherein said cyclic ester monomer isepsilon-caprolactone.
 6. An article according to claim 1 in the form ofa suture or ligature.
 7. An article according to claim 6 in the form ofa needle and suture combination.
 8. A sterile surgical articlefabricated from a synthetic absorbable copolymer comprising a proportionof sequential units having the formula: ##STR3## and a proportion ofsequential units having the formula: ##STR4## wherein formula (II)consists of up to about 50% by weight.
 9. An article of claim 8 having amelting point of about 217° C. to 221° C. as described by the peak in adifferential scanning calorimeter operating at a heating rate of 10° C.per minute.
 10. An article of claim 9 having an inherent viscosity ofabout 0.5 dl/g. to 2 dl/g.
 11. An article of claim 10 having an inherentviscosity of about 0.7 dl/g to 1.2 dl/g.
 12. An article of claim 8 or 9or 11 wherein formula (II) consists of up to about 35% by weight.
 13. Anarticle of claim 12 wherein formula (II) consists of between about 10%to 20% by weight.
 14. An article according to claim 8 in the form of asuture or ligature.
 15. An article according to claim 14 in the form ofa needle and suture combination.
 16. A method of retaining living tissuein a desired relationship during a healing process by positioning andemplacing living tissue with a sterile surgical article of claim
 8. 17.A method of closing a wound of living tissue which comprises sewing theedges of the wound with a needled suture of claim 15.